Coexposure of mice to trovafloxacin and lipopolysaccharide, a model of idiosyncratic hepatotoxicity, results in a unique gene expression profile and interferon gamma-dependent liver injury.
The antibiotic trovafloxacin (TVX) has caused severe idiosyncratic hepatotoxicity in people, whereas levofloxacin (LVX) has not. Mice cotreated with TVX and lipopolysaccharide (LPS), but not with LVX and LPS, develop severe hepatocellular necrosis. Mice were treated with TVX and/or LPS, and hepatic gene expression changes were measured before liver injury using gene array. Hepatic gene expression profiles from mice treated with TVX/LPS clustered differently from those treated with LPS or TVX alone. Several of the probe sets expressed differently in TVX/LPS-treated mice were involved in interferon (IFN) signaling and the janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway. A time course of plasma concentrations of IFN-gamma and interleukin (IL)-18, which directly induces IFN-gamma production, revealed that both cytokines were selectively increased in TVX/LPS-treated mice. Both IL-18(-/-) and IFN-gamma(-/-) mice were significantly protected from TVX/LPS-induced liver injury. In addition, IFN-gamma(-/-) mice had decreased plasma concentrations of tumor necrosis factor-alpha, IL-18, and IL-1beta when compared to wild-type mice. In conclusion, the altered expression of genes involved in IFN signaling in TVX/LPS-treated mice led to the finding that IL-18 and IFN-gamma play a critical role in TVX/LPS-induced liver injury.
Shaw
Patrick J
PJ
Department of Pharmacology and Toxicology, National Food Safety and Toxicology Center, Center for Integrative Toxicology, Michigan State University, East Lansing, Michigan 48824, USA.
Ditewig
Amy C
AC
Waring
Jeffrey F
JF
Liguori
Michael J
MJ
Blomme
Eric A
EA
Ganey
Patricia E
PE
Roth
Robert A
RA
D000704:Analysis of Variance; D000818:Animals; D056486:Chemical and Drug Induced Liver Injury; D005260:Female; D024841:Fluoroquinolones / Q000008:administration & dosage / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects; D022781:Hepatocytes / Q000187:drug effects*; D007249:Inflammation / Q000378:metabolism; D007371:Interferon-gamma / Q000097:blood / Q000378:metabolism*; D020382:Interleukin-18 / Q000097:blood / Q000378:metabolism; D053612:Janus Kinases / Q000378:metabolism; D064704:Levofloxacin; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000494:pharmacology*; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008107:Liver Diseases / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009287:Naphthyridines / Q000008:administration & dosage / Q000494:pharmacology*; D009336:Necrosis / Q000378:metabolism; D015242:Ofloxacin / Q000008:administration & dosage / Q000494:pharmacology*; D020411:Oligonucleotide Array Sequence Analysis; D050791:STAT Transcription Factors / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects
D024841:Fluoroquinolones; D020382:Interleukin-18; D008070:Lipopolysaccharides; D009287:Naphthyridines; D050791:STAT Transcription Factors; D064704:Levofloxacin; D007371:Interferon-gamma; C080163:trovafloxacin; D015242:Ofloxacin; D053612:Janus Kinases